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Title: Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity
Authors: Ku, Cheng Lung
Von Bernuth, Horst
Picard, Capucine
Zhang, Shen Ying
Chang, Huey Hsuan
Yang, Kun
Chrabieh, Maya
Issekutz, Andrew C.
Cunningham, Coleen K.
Gallin, John
Holland, Steven M.
Roifman, Chaim
Ehl, Stephan
Smart, Joanne
Tang, Mimi
Barrat, Franck J.
Levy, Ofer
McDonald, Douglas
Day-Good, Noorbibi K.
Miller, Richard
Takada, Hidetoshi
Hara, Toshiro
Al-Hajjar, Sami
Al-Ghonaium, Abdulaziz
Speert, David
Sanlaville, Damien
Li, Xiaoxia
Geissmann, Frédéric
Vivier, Eric
Maródi, László
Garty, Ben Zion
Chapel, Helen
Rodriguez-Gallego, Carlos 
Bossuyt, Xavier
Abel, Laurent
Puel, Anne
Casanova, Jean Laurent
UNESCO Clasification: 32 Ciencias médicas
3205 Medicina interna
Keywords: IRAK-4–deficient
Issue Date: 2007
Journal: Journal of Experimental Medicine 
Abstract: Human interleukin (IL) 1 receptor–associated kinase 4 (IRAK-4) deficiency is a recently discovered primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3– and TLR4–interferon (IFN)-a/b pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK-4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells (PBMCs) did not induce the 11 non-IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly(I:C). The patients' individual cell subsets from both myeloid (granulocytes, monocytes, monocyte-derived dendritic cells [MDDCs], myeloid DCs [MDCs], and plasmacytoid DCs) and lymphoid (B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly(I:C) and lipopolysaccharide in MDCs and MDDCs. Most patients (22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent (13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease (9 out of 28; 32%). Almost half of the patients died (12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK-4–dependent TLRs and IL-1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK-4–dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.
ISSN: 0022-1007
DOI: 10.1084/jem.20070628
Source: Journal of Experimental Medicine[ISSN 0022-1007],v. 204, p. 2407-2422
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